Cytosine-adenine protonated wobble
4 17.12 Nonstandard base pairings can occur as a result of the flexibility in DNA structure. Thymine and guanine can pair through wobble between normal bases. Cytosine and adenine can pair through wobble when adenine is protonated (has an extra hydrogen).
able to pair because of flexibility in the DNA helical structure (Figure 17.12). These structures have been detected in DNA molecules and are now thought to be responsible for many of the mispairings in replication.
When a mismatched base has been incorporated into a newly synthesized nucleotide chain, an incorporated error is said to have occurred. Suppose that, in replication, thymine (which normally pairs with adenine) mispairs with guanine through wobble (Figure 17.13). In the next round of replication, the two mismatched bases separate, and each serves as template for the synthesis of a new nucleotide strand. This time, thymine pairs with adenine, producing another copy of the original DNA sequence. On the other strand, however, the incorrectly incorporated gua-nine serves as the template and pairs with cytosine, producing a new DNA molecule that has an incorporated error—a
C-G pair in place of the original T-A pair (a T-A:C-G base substitution). The original incorporated error leads to a replication error, which creates a permanent mutation, because all the base pairings are correct and there is no mechanism for repair systems to detect the error.
Mutations due to small insertions and deletions also may arise spontaneously in replication and crossing over. Strand slippage may occur when one nucleotide strand forms a small loop (< Figure 17.14). If the looped-out nucleotides are on the newly synthesized strand, an insertion results. At the next round of replication, the insertion will be incorporated into both strands of the DNA molecule. If the looped-out nucleotides are on the template strand, then there is a deletion on the newly replicated strand, and this deletion will be perpetuated in subsequent rounds of replication.
During normal crossing over, the homologous sequences of the two DNA molecules align, and crossing over produces no net change in the number of nucleotides in either molecule. Misaligned pairing may cause unequal crossing over, which results in one DNA molecule with an insertion and the other with a deletion (Figure 17.15). Some DNA sequences are more likely than others to undergo strand slippage or unequal crossing over. Stretches of repeated sequences, such as trinucleotide repeats or homopolymeric repeats (more than five repeats of the same base in a row), are prone to strand slippage. Stretches with more repeats are more likely to undergo strand slippage. Duplicated or repetitive sequences may misalign during pairing, leading to unequal crossing over. Both strand slippage and unequal crossing over produce duplicated copies of sequences, which in turn promote further strand slippage and unequal crossing over. This chain of events may explain the phenomenon of anticipation often observed for expanding trinucleotide repeats.
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